CD8 T cells play an essential role in the adaptive immune response against intracellular pathogens and cancerous growths. The ability of CD8 T cells to protect the host declines with age due to decrease in the number of nave cells and in the diversity of the T cell receptor (TCR) repertoire, and increase in the number of dysfunctional memory cells such as CD28- CD8 T cells. Accumulation of CD28- CD8 T cells with aging presents one of the most consistent changes in human immune cells. The age-associated increase of CD28- CD8 T cells has been attributed as a consequence of repeated or chronic antigenic stimulations. More recent studies also suggest that homeostatic cytokines such as IL-15 can also induce CD28- CD8 T cells in vitro. However, the underlying mechanism of this age-associated change is not fully understood. We recently analyzed the global gene expression profiles of CD8 T cell subsets from nave to memory (CD28+ to CD28-) cells and the growth of CD28+ and CD28- CD8 memory T cells in response to homeostatic cytokine interleukin 15 (IL-15). At the gene expression level, one of the most striking changes is the altered expression of some co-stimulatory receptors and various NK cell receptors in CD28- CD8 T cells. Furthermore, CD28- CD8 T cells appear to have a normal proliferation response to IL-15 in vitro. Interestingly, IL-15 is also capable of inducing stable loss of CD28 expression in actively dividing CD28+CD8 memory T cells. Together, these findings provide the gene expression features of CD28- CD8 T cells that differ from their CD28+ counterparts and suggest a possible role of IL-15 in the increase of CD28-CD8 T cells that occurs with aging.